The Relationship of Redox With Hallmarks of Cancer: The Importance of Homeostasis and Context

Abstract

Redox homeostasis is a lifelong pursuit of cancer cells. Depending on the context, reactive oxygen species (ROS) exert paradoxical effects on cancers; an appropriate concentration stimulates tumorigenesis and supports the progression of cancer cells, while an excessive concentration leads to cell death. The upregulated antioxidant system in cancer cells limits ROS to a tumor-promoting level. In cancers, redox regulation interacts with tumor initiation, proliferation, metastasis, programmed cell death, autophagy, metabolic reprogramming, the tumor microenvironment, therapies, and therapeutic resistance to facilitate cancer development. This review discusses redox control and the major hallmarks of cancer.

Keywords: Nrf2; ROS; antioxidant response; hallmarks of cancer; redox homeostasis.

Figure 1

The major reactive oxygen species ( $O_{2^{-}}$ , H₂O₂, ONOO^-) and their sites of production within cells. The main endogenous sources of ROS are mitochondrial electron transport chain (ETC) and NADPH oxidases (NOXs). In addition, peroxisome and endoplasmic reticulum (ER) also generate ROS. Transition metal ion iron nonenzymatically catalyzes ROS generation via the Fenton reaction.

Figure 2

The effects of reactive oxygen species (ROS) and Nrf2 on cancer. In the early stages of cancer, appropriate levels of ROS act as initiators and mediators of carcinogenesis and cancer promotion. In the advanced stages of cancer, excessive ROS promote cancer cell death and are detrimental to cancer progression. In normal cells and precancerous cells, controlled activation of Nrf2 decreases ROS and inhibits cancer initiation. In malignant and metastatic cells, sustained activation of Nrf2 counteracts oxidative stress to promote cancer progression.

Figure 3

Relationship of redox with the major hallmarks of cancer. Redox regulation is associated with the hallmarks of cancer, maintaining redox homeostasis and impacting cancer progression.

Figure 4

Signaling molecules and pathways regulating ferroptosis and gemcitabine resistance in cancer cells. Ferroptosis is a form of cell death driven by iron accumulation and lipid peroxidation. The acyl-CoA synthetase long-chain family member 4 (ACSL4)-lysophosphatidylcholine acyltransferase 3 (LPCAT3)-arachidonate lipoxygenases (ALOXs) pathway enzymatically mediates oxidation of polyunsaturated fatty acids (PUFAs) of the plasma membrane to phospholipid hydroperoxide (PLOOH), ultimately leading to ferroptosis. Nuclear receptor coactivator 4 (NCOA4) induces ferritinophagy to increase intracellular iron, promoting non-enzymatic lipid peroxidation and inducing ferroptosis. However, glutathione peroxidase 4 (GPX4) inhibits lipid peroxidation together with glutathione (GSH), which prevents ferroptosis. Intracellular levels of GSH are maintained by the system X _{c ⁻} (solute carrier family 7 member 11, SLC7A11 and solute carrier family 3 member 2, SLC3A2), which accepts extracellular cystine for GSH synthesis. In addition, apoptosis-inducing factor mitochondrial 2 (AIFM2) maintains a reduced state of coenzyme Q₁₀ (CoQ10H2) to prevent lipid peroxidation and ferroptosis. Therefore, upregulation of SLC7A11, GSH, GPX4, and AIFM2 expression renders cancer cells resistant to ferroptosis. Gemcitabine can increase reactive oxygen species (ROS) production via nuclear factor kappa-B (NF-κB)-p22^-phox-nicotinamide adenine dinucleotide phosphate oxidase (NOX) pathway in pancreatic ductal adenocarcinoma (PDAC) cells to induce ferroptosis. Activation of nuclear erythroid 2-related factor (Nrf2) decreases ROS and suppresses ferroptosis.